Impact of APOE on endothelial cell proteomes in Alzheimer's disease

APOE 对阿尔茨海默病内皮细胞蛋白质组的影响

• 批准号: 10606847
• 负责人: Aleksandra Maria Wojtas
• 金额: $ 7.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606847
• 关键词: APP-PS1; Abeta clearance; Acceleration; Affect; Age; Age Months; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Apolipoprotein E; Autopsy; Biological Markers; Biotin; Biotinylation; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Blood flow; Brain; Brain region; Cells; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Collection; Coupled; Cre lox recombination system; Data; Dementia; Deposition; Diagnosis; Disease; Disease Progression; Endothelial Cells; Endothelium; Exhibits; Functional disorder; Genes; Genetic Predisposition to Disease; Genome; Genotype; Goals; Health; Histologic; Human; Immunohistochemistry; Impaired cognition; Impairment; Individual; Label; Ligase; Link; Mass Spectrum Analysis; Mediating; Memory; Molecular; Mus; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Pathway interactions; Play; Proteins; Proteome; Proteomics; Research; Resolution; Risk Factors; Role; Sampling; Structure; Techniques; Technology; Testing; Tissues; Variant; Vascular Diseases; Western Blotting; Work; abeta accumulation; abeta deposition; amyloid pathology; apolipoprotein E-3; asymptomatic Alzheimer' s disease; blood-brain barrier permeabilization; brain endothelial cell; brain parenchyma; brain tissue; cell type; cerebrovascular; cerebrovascular pathology; density; disease phenotype; genome wide association study; high risk; in vivo; innovation; insight; mouse model; new therapeutic target; non-demented; normal aging; novel; protein aggregation; religious order study; risk variant; sex; single-cell RNA sequencing; tau aggregation; therapeutic biomarker; therapeutic target; transcriptomics

ABSTRACT (PROJECT SUMMARY) Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that results in deposition of amyloid-b (Ab) peptide in brain parenchyma and cerebral blood vessels as cerebral amyloid angiopathy (CAA). Genome- wide association studies (GWAS) have identified numerous genes altering AD risk with the e4 allele of apolipoprotein E (APOE4) showing the strongest association with AD and CAA. APOE4 modulates amyloid accumulation in cerebrovasculature and impacts the efficiency of Ab clearance from the brain. In addition, APOE4 carriers exhibit accelerated breakdown of the blood-brain barrier (BBB) and higher risk for cerebrovascular dysfunction during normal aging. However, the underlying mechanisms of this genetic susceptibility on cerebrovascular function and pathology are still poorly understood. Recent work from our group revealed APOE-driven protein perturbations associated with endothelial cells in the postmortem brain tissue from AD individuals. Yet, these observations come from bulk brain tissue limiting the ability to dissect cell-type specific proteomic changes. Thus, the major goal of this proposal is to molecularly define the endothelial cells in the context of APOE-associated amyloidosis. I hypothesize that APOE4 genotype directly impacts endothelial proteome leading to the BBB dysfunction and breakdown. In Aim 1, I will perform an unbiased proteomic analysis of isolated cerebral blood vessels from cortical tissues of AD, AD with severe CAA, asymptomatic AD (AsymAD, individuals exhibiting amyloid and tau accumulation in the brain with no cognitive decline), and non-demented control individuals. I will further apply integrative analysis to the brain vascular proteomes and previously generated proteomic data of cerebrospinal fluid (CSF) to identify AD CSF biomarkers that mirror pathological changes of the cerebrovasculature. In Aim 2, I will explore in vivo effect of APOE and amyloid on endothelial cell proteome by taking advantage of highly innovative, recently developed by our group approach that allows for Cell-type specific In-vivo Biotinylation of Proteins followed by mass-spectrometry (CIBOP-MS). Dissecting proteomes of endothelial cells in a disease setting will be a conceptual advancement and a crucial step towards understanding the mechanisms underlying AD-related BBB breakdown, diminished blood flow, and pathological accumulation of amyloid in the cerebrovasculature.

摘要（项目总结） 阿尔茨海默病（Alzheimer's disease，AD）是一种进行性神经退行性疾病， (Ab)脑淀粉样血管病（CAA）是脑实质和脑血管中的一种多肽。基因组- 广泛关联研究（GWAS）已经确定了许多改变AD风险的基因， 载脂蛋白E（APOE 4）与AD和CAA的相关性最强。APOE 4调节淀粉样蛋白 抗体在脑血管系统中蓄积，并影响Ab从脑中清除的效率。此外，本发明还提供了一种方法， APOE 4携带者表现出血脑屏障（BBB）的加速破坏和更高的风险。 正常衰老过程中的脑血管功能障碍。然而，这种遗传的潜在机制 易感性对脑血管功能和病理学影响仍知之甚少。我们小组最近的工作 揭示了APOE驱动的蛋白质扰动与死后脑组织中的内皮细胞相关， AD个体。然而，这些观察结果来自大块脑组织，限制了解剖细胞类型特异性的能力。 蛋白质组变化因此，该提议的主要目标是从分子上定义血管内皮细胞。 APOE相关淀粉样变性的背景。我假设APOE 4基因型直接影响内皮细胞 蛋白质组导致血脑屏障功能障碍和崩溃。在目标1中，我将进行无偏的蛋白质组学分析 从AD、患有严重CAA的AD、无症状AD（AsymAD， 在脑中表现出淀粉样蛋白和tau积累而没有认知下降的个体），和非痴呆的 控制个人。我将进一步应用整合分析脑血管蛋白质组和以前的 生成脑脊液（CSF）的蛋白质组学数据，以鉴定反映病理学特征的AD CSF生物标志物 血管的变化。目的二探讨APOE和淀粉样蛋白对内皮细胞的影响 蛋白质组通过利用高度创新的优势，最近由我们的小组开发的方法， 细胞类型特异性蛋白质体内生物素化，随后进行质谱分析（CIBOP-MS）。解剖 内皮细胞的蛋白质组在疾病环境中将是一个概念上的进步和关键一步， 了解AD相关的BBB破坏、血流量减少和病理学 淀粉样蛋白在血管中的积累。